Dopamine (DA) is a monoaminergic neurotransmitter that has been implicated in multiple neurological and psychiatric disorders in the CNS. The various actions of DA on target neurons are mediated via prototypical 7-transmembrane G protein-coupled receptors that couple to various effectors through G protein-dependent mechanisms. Our previous work has demonstrated that in the striatum, DA D2 receptors (D2R) mediate some of their actions through the Akt/GSK3 signaling pathway in a G protein-independent fashion via formation of a ?-arrestin 2/Akt/PP2A signaling complex leading to inhibition of Akt and the consequent activation of GSK3. Recent investigations in animals and humans have suggested an important role for the Akt/GSK3 signaling pathway in behavioral manifestations of elevated DA tone and in conditions like schizophrenia or mania. Clinically effective antipsychotic drugs that bind D2Rs show a high propensity to engage the ?-arrestin 2-mediated pathway, and the mood stabilizer lithium interferes with this pathway by inhibiting the stability of the ?-arrestin 2/Akt/PP2A signaling complex. Despite these exciting cellular results, the functional consequences of this pathway in vivo are poorly understood. The overall objective of this research is to generate a series of animal models in which the functioning of the pathway downstream of D2Rs can be precisely investigated at different levels downstream of ?-arrestin 2. Aim 1: We will examine the role of GSK3? and ?-catenin in the actions of DA by selectively manipulating them in postsynaptic D1R- and D2R-expressing neurons of the striatal efferent pathways. Aim 2: We will determine the contribution of ?-arrestin 2 by selectively inactivating and rescuing its function in the same postsynaptic neurons. Aim 3: Finally, we will engineer mouse lines that selectively express either wild type or D2Rs that can selectively couple through either a G protein- or a ?-arrestin 2-dependent mechanism in these same postsynaptic neurons. We anticipate that the biochemical, cell biological and behavioral analyses of these animal models will provide a unique understanding of how this novel D2R signaling mechanism transduces the actions of DA in striatum and that our results will provide novel insights into the development of new therapeutic agents. PUBLIC HEALTH RELEVANCE: The neurotransmitter dopamine has been implicated in multiple psychiatric disorders including Parkinson's and Huntington's diseases, schizophrenia, attention deficit-hyperactivity disorder, Tourette syndrome, mania, addiction and affective disorders. We have previously identified a novel signaling mechanism transduced through dopamine D2-like receptors. Since these receptors are primary targets for antipsychotic drugs, and because these drugs have wide application in psychiatry, this new signaling pathway may be important both in the etiology of these conditions and in their therapeutic management. The targeting of components in this pathway through generation of genetically-modified mice should clarify the in vivo role of this pathway under normal and pathophysiological actions of dopamine transmission and provide unique insights into the development of novel pharmacotherapies to treat the various psychiatric conditions.